title: Molecular basis of protein S deficiency in China.
abstract: Protein S (ProS) is a physiological inhibitor of coagulation with an important function in the down-regulation of thrombin generation. ProS deficiency is a major risk factor for venous thrombosis. This study enrolled 40 ProS-deficient probands to investigate the molecular basis of hereditary ProS deficiency in Chinese patients. A mutation analysis was performed by resequencing the PROS1 gene. Large deletions were identified by multiplex ligation-dependent probe amplification (MLPA) analysis. A total of 20 different mutations, including 15 novel mutations, were identified in 21 of the 40 index probands. Small mutations were detected in 18 (45.0%) probands, and large deletions were found in 3 (7.5%) probands, leaving 19 (47.5%) patients without causative variants. To evaluate the functional consequences of 2 novel missense variants, ex vivo thrombin-generation assays, bioinformatics tools, and in vitro expression studies were employed. The p.Asn365Lys ProS variant was found to have moderately impaired secretion and reduced activated protein C cofactor activity. In contrast, the p.Pro410His mutant appeared to have severely impaired secretion but full anticoagulant activity. This study is the largest investigation of ProS deficiency in China and the first investigation of the influence of Type I ProS missense mutations on the global level of coagulation function. The p.K196E mutation, which is common in the neighboring Japanese population, was not found in our Chinese population, and null mutations were common in our Chinese population but not common in Japan. Further genetic analysis is warranted to understand the causes of ProS deficiency in patients without a genetic explanation.
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Hubei Clinical and Research Center of Thrombosis and Haemostasis, Wuhan, Hubei, China; Targeted Biotherapy Key Laboratory of Ministry of Education, Wuhan, Hubei, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Jian
authors.forename: Naotaka
authors.initials: N
authors.lastname: Hamasaki
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
authors.forename: Hua-Fang
authors.initials: HF
authors.lastname: Wang
authors.forename: Xuan
authors.initials: X
authors.lastname: Lu
authors.forename: Qing-Yun
authors.initials: QY
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D044466:Asian People; D001798:Blood Proteins / Q000235:genetics* / Q000378:metabolism; D002681:China; D004252:DNA Mutational Analysis; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D020125:Mutation, Missense; D011486:Protein C / Q000235:genetics / Q000378:metabolism; D017293:Protein S; D018455:Protein S Deficiency / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism
chemical_list: D001798:Blood Proteins; C523390:PROS1 protein, human; D011486:Protein C; D017293:Protein S